Histotripsy Group

On March 25, Zhen Xu, PhD, associate professor in the Department of Biomedical Engineering at the University of Michigan, was awarded the 2019 Andrew J. Lockhart Memorial Prize by the Focused Ultrasound Foundation.

Zhen Xu 400

The $75,000 annual prize is awarded to an investigator to recognize outstanding contributions in advancing cancer treatment using focused ultrasound and the potential for continued achievements in the field. The prize was established in 2017 by the family and friends of Andrew J. Lockhart, who passed away in 2016 at the age of 39 after a hard-fought battle with cholangiocarcinoma, a malignant cancer affecting the biliary system.

The primary focus of Dr. Xu’s research is on developing and using histotripsy to treat cancer and neurological diseases. She is one of the original inventors of histotripsy, a process that uses focused ultrasound to mechanically disrupt target tissue, as opposed to thermal ablation – or heating – of tissue.

Dr. Xu’s laboratory at the University of Michigan has pioneered the use of histotripsy in the fight against cancer, leading to a clinical trial in Europe to treat liver cancer. More recently, the group’s research has led to trials for histotripsy treatment of brain cancer and histotripsy for immunotherapy.

“Histotripsy is the first image-guided technique using focused ultrasound to destroy tissue noninvasively, without heating and without the use of ionizing radiation. It works by mechanically liquefying the target cancer tissue and demonstrates the potential to increase accuracy and reduce off-target damage for cancer treatment when compared to radiation or thermal-based approaches,” said Dr. Xu. “Now, we believe that histotripsy can induce a potent immune response, and we hope that this ultrasound technique can also be extended beyond local tumor ablation to treat tumor metastases.”

Andrew Lockhart’s parents, Terry and Gene, said, “This award is intended to recognize and encourage exactly the kind of groundbreaking research that Dr. Xu is conducting. It will take revolutionary ideas to find effective therapies for hard-to-treat cancers like the one that claimed Andrew. We believe that Dr. Xu and other innovators will hasten the advent of such interventions.

On the same day she received the award, Dr. Xu conducted a webinar on histotripsy, which was available via live stream, as well as on the Foundation’s social media channels. During the webinar, Dr. Xu discussed the basic mechanism, instrumentation, bioeffects, and applications of histotripsy. She also covered the latest preclinical and clinical trial results of histotripsy for the treatment of cancer and neurological diseases.

“The magnanimity of the Lockhart family is having a profound effect on the Foundation and on the field of focused ultrasound research,” said Founder and Chairman of the Focused Ultrasound Foundation, Neal F. Kassell, MD. “This prize is a tremendous honor and recognition for Zhen Xu and the previous recipients – and it is a heartfelt tribute to the memory of the Lockhart’s beloved son, Andrew.”

This is the third time the Andrew J. Lockhart Memorial Prize has been awarded. In 2017, the inaugural prize was given to Richard Price, PhD, professor of biomedical engineering, radiology and radiation oncology at the University of Virginia. The 2018 Lockhart Prize went to Graeme Woodworth, MD, professor of neurosurgery at the University of Maryland School of Medicine. A call for nominations for the 2020 prize will be announced later this spring.

About the Focused Ultrasound Foundation
The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of this noninvasive technology. The Foundation works to clear the path to global adoption by coordinating and funding research, fostering collaboration, and building awareness among patients and professionals. Since its establishment in 2006, the Foundation has become the largest nongovernmental source of funding for focused ultrasound research. 

 

Non-invasive Ultrasonic Tissue Fractionation for Treatment of Benign Disease and Cancer -“Histotripsy”

Ultrasound has been widely known for diagnostic imaging. The most recent studies suggest that it also has potential to be developed as a non-invasive therapy tool. Ultrasound has the ability to focus energy deep within the human body without damaging the overlying tissue. If the energy is sufficient, significant bioeffects (e.g. tissue necrosis and tissue fractionation) can be achieved. This ability of ultrasound is suited perfectly for many types of non-invasive therapy.

Since 2001, our team has been developing a new technique to achieve mechanical fractionation of tissue structure using a number of short (several μsec), high intensity ultrasound pulses. The ultrasound intensity used is hundreds of times higher than regular diagnostic imaging and similar to “lithotripsy” which has been used for breaking down kidney stones. We have called this technique “histotripsy”. “Histo” means soft tissue in Greek, and “tripsy” means breakdown. At a fluid-tissue interface, histotripsy results in localized tissue removal with sharp boundaries, which we use to remove cardiac tissue in treatment of congenital heart disease. In bulk tissue, histotripsy produces mechanical fragmentation of tissue resulting in a liquefied cored with very sharply demarcated boundaries. Histology demonstrates treated tissue within the lesion is fragmented to subcelluar level surrounded by an almost imperceptibly narrow margin of cellular injury. As shown in the pictures on of right, at the lesion boundary, half of the cell is cut off, and the other half is still intact. Histotripsy has vast clinical applications where precise tissue ablation and removal are needed (e.g., tumor treatment).

The mechanism of histotripsy is acoustic cavitation – ultrasound pressure changes form microbubbles in human body and energetic microbubble activities fragment and subdivide tissue resulting in cellular destruction. Compared to non-invasive thermal therapy, histotripsy has some important advantages including the following: 1) Microbubbles produced at the ultrasound focus, shown as bright spots on ultrasound imaging, allow the operator to see the targeted volume; 2) Energetic microbubble activities can be seen on imaging and provide real-time feedback, so the operator knows what is going on; 3) After treatment, the lesion appears darker on ultrasound imaging, so that the operator knows what has been done; and 4) Histotripsy technique can produce lesions in a very controlled and precise manner. We believe and hope that, in the near future, non-invasive image guided cavitational ultrasound therapy (histotripsy) can be provided to clinicians as a non-invasive surgery tool to significantly improve the quality of currently available surgery and therapy modalities. Current clinical targets are: breast cancer, prostate cancer, several cardiac applications, and various benign diseases including prostatic “BPH” and breast fibroadenoma.

Histotripsy Mechanism – Cavitation Bubble Dynamics

There are two mechanisms in which a cavitation cloud can be generated. In the first mechanism, termed the “shock scattering mechanism” of cloud initiation, a dense bubble cloud can be formed from a single multi-cycle histotripsy pulse (e.g., 3 – 20 cycles) using shock scattering from single bubbles formed and expanded from the initial cycles of the pulse. In this process of cloud initiation, initial single bubbles are likely formed from micron-sized heterogeneous nuclei in the focus. These initial bubbles act as a pressure release surface wherein the following positive pressure half cycles, usually very high peak pressure shock fronts, are inverted and superimposed on the incident negative pressure phase to form extremely high negative pressures that produce a dense cavitation cloud growing back toward the transducer. Using the shock scattering mechanism, histotripsy bubble clouds are initiated at negative pressure magnitudes ranging from 10-28 MPa.

The second mechanism for histotripsy cavitation cloud formation termed the “intrinsic threshold mechanism”, in which a single pulse with only one high amplitude negative phase is used to generate bubble clouds using only the peak negative pressure of the incident wave. With the extremely short pulse, cavitation initiation depends solely on the negative pressure when it exceeds a threshold intrinsic to the medium, without the contributions from shock scattering, resulting in bubble cloud formation matching the portion of the focal region above the intrinsic threshold. In the previous study by Maxwell et al., an intrinsic threshold of approximately 26-30 MPa was observed for water based soft tissues and tissue phantoms using a 1.1 MHz histotripsy transducer, while the threshold for tissue containing lipids was significantly lower (15.4 MPa for fat).

It is believed that the rapid expansion and collapse of the cavitation bubbles produce high mechanical strain and stress repeated over many pulses to disrupt the cells immediately surrounding the cavitation bubbles.

  1. Xu Z, Ludomirsky A, Eun LY, Hall TL, Tran BC, Fowlkes JB, Cain CA. Controlled ultrasound tissue erosion. Institute of Electrical and Electronics Engineers (IEEE) Transaction on Ultrasonics, Ferroelectrics and Frequency Control, 2004;51(6):726-36.
  2. Parsons JE, Cain CA, Abrams GD, Fowlkes JB. Pulsed cavitational ultrasound therapy for controlled tissue homogenization. Ultrasound Med Biol. 2006;32(1):115-29.
  3. Maxwell AD, Wang T-Y, Cain CA, Fowlkes JB, Sapozhnikov OA, Bailey MR, Xu Z. Cavitation clouds created by shock scattering from bubbles during histotripsy. Journal of The Acoustical Society of America. 2011;130(4):1888-98.
  4. Maxwell AD, Cain CA, Hall TL, Fowlkes JB, Xu Z. Probability of cavitation for single ultrasound pulses applied to tissues and tissue-mimicking materials. Ultrasound in Medicine and Biology, 2013;39(3):449-65.
  5. Vlaisavljevich E, Maxwell A, Mancia L, Johnsen E, Cain C, Xu Z. Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment. Ultrasound Med Biol. 2016;42(10):2466-77. PMCID: 5010997.
  6. Vlaisavljevich E, Xu Z, Maxwell A, Mancia L, Zhang X, Lin KW, Duryea A, Sukovich J, Hall T, Johnsen E, Cain C. Effects of Temperature on the Histotripsy Intrinsic Threshold for Cavitation. IEEE Trans Ultrason Ferroelectr Freq Control. 2016;63(8):1064-77.
  7. Vlaisavljevich E, Gerhardson T, Hall T, Xu Z. Effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior. Phys Med Biol. 2017;62(4):1269-90.